Formulations and methods for providing prolonged local anesthesia

ABSTRACT

A formulation and methods for inducing sustained regional local anesthesia in a patient comprising a substrate comprising a local anesthetic and an effective amount of a biocompatible, biodegradable, controlled release material prolonging the release of the local anesthetic from the substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and a pharmaceutically acceptable, i.e., non-toxic, non-glucocorticoid augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable from the substrate without the augmenting agent.

This application is a continuation of Ser. No. 09/522,572 filed on Mar.10, 2000 now abandoned, which is a continuation of Ser. No. 09/342,964,which was filed on Jun. 29, 1999, now U.S. Pat. No. 6,514,516, which isa continuation of Ser. No. 08/793,861, filed Jun. 16, 1997, now U.S.Pat. No. 5,942,241, which was filed as International ApplicationPCT/US96/10439 on Jun. 7, 1996 and published as WO 96/41616 on Dec. 27,1996, and claiming the right of priority of Provisional Application No.60/000,105, filed on Jun. 9, 1995.

BACKGROUND OF THE INVENTION

The present invention is related to biodegradable controlled releaseformulations for the administration of locally active drugs, inparticular, local anesthetics and compositions and methods foraugmenting the potency and duration of the same.

While compounds utilized as general anesthetics reduce pain by producinga loss of consciousness, local anesthetics act by producing a loss ofsensation in the localized area of administration in the body. Themechanism by which local anesthetics induce their effect, while nothaving been determined definitively, is generally thought to be basedupon the ability to interfere with the initiation and transmission ofthe nerve impulse. The duration of action of a local anesthetics isproportional to the time during which it is in actual contact with thenervous tissues. Consequently, procedures or formulations that maintainlocalization of the drug at the nerve greatly prolong anesthesia.

All local anesthetics are toxic, i.e., potentially toxic, and thereforeit is of great importance that the choice of drug, concentration, rateand site of administration, as well as other factors, be considered intheir use. On the other hand, a local anesthetic must remain at the sitelong enough to allow sufficient time for the localized pain to subside.

Different devices and formulations are known in the art foradministration of local anesthetics. For example, U.S. Pat. Nos.4,725,442 and 4,622,219 (Haynes) are directed to microdroplets ofmethoxyflurane-containing microdroplets coated with a phospholipidprepared by sonication, which are suitable for intradermal orintravenous injection into a patient for inducing local anesthesia. Suchmicrodroplets are said to cause long-term local anesthesia when injectedintradermally, giving a duration of anesthesia, considerably longer thanthe longest acting conventional local anesthetic (bupivacaine).

U.S. Pat. No. 5,188,837 (Domb) relates to a microsuspension systemcontaining lipospheres having a layer of a phospholipid imbedded ontheir surface. The core of the liposphere is a solid substance to bedelivered, or the substance to be delivered is dispersed in an inertvehicle. The substance to be delivered can be, e.g., nonsteroidalanti-inflammatory compounds, local anesthetics, water insolublechemotherapeutic agents and steroids.

Other formulations directed to injectable microcapsules, etc. are known.For example, U.S. Pat. No. 5,061,492 related to prolonged releasemicrocapsules of a water-soluble drug in a biodegradable polymer matrixwhich is composed of a copolymer of glycolic acid and a lactic acid. Themicrocapsules are prepared as an injectable preparation in apharmaceutically acceptable vehicle. The particles of water soluble drugare retained in a drug-retaining substance dispersed in a matrix of thelactic/glycolic acid copolymer in a ratio of 100/1 to 50/50 and anaverage molecular weight of 5,000-200,000. The injectable preparation ismade by preparing a water-in-oil emulsion of aqueous layer of drug anddrug retaining substance and an oil layer of the polymer, thickening andthen water-drying.

U.S. Pat. No. 4,293,539 (Ludwig, et al.) is directed to controlledrelease formulations comprised of a microbial agent dispersed throughouta copolymer derived from lactic acid and glycolic acid. The copolymer isderived from 60-95% lactic acid and 40-5% glycolic acid by weight, andhas a molecular weight of 6,000-35,000. An effective amount of thecopolymeric formulation is administered by subcutaneous or intramuscularadministration.

WO 94/05265 describes improved biodegradable controlled release systemsConsisting of a polymeric matrix incorporating a local anesthetic forthe prolonged administration of the local anesthetic agent. The devicesare selected on the basis of their degradation profiles: release of thetopical anesthetic in a linear, controlled manner over the period ofpreferably two weeks and degradation in vivo with a half-life of lessthan six months, more preferably two weeks; to avoid localizedinflammation. The disclosure states that an anti-inflammatory can beincorporated into the polymer with the local anesthetic to reduceencapsulation for optimal access of drug to its site of action. Theanti-inflammatories that are said to be useful include steroids such asdexamethasone, cortisone, prednisone, and others routinely administeredorally or by injection.

Several non-glucocorticoids have been reported to prolong the action oflocal anesthetics. Epinephrine in immediate release form is art known tobriefly prolong the action of immediate release local anesthetics byinducing vasoconstriction adjacent to the site of injection. However,the duration of prolongation provided by immediate release epinephrineis on the order of about an hour, at best, in a highly vascularizedtissue. This strategy is also severely limited by the risk of gangrenedue to prolonged impairment of blood flow to local tissues. Dextrans andalkalinizing agents have also been suggested as local anesthesiaprolonging agents, but have heretofore been reported to be ineffectivefor this purpose (Bonica et al., 1990, “Regional Analgesia With LocalAnesthetics” THE MANAGEMENT OF PAIN, Second Edition, Volume II,Published, Lea & Febiger, Chapter 94, pages 1890-1892).

Colchicine has been shown to suppress injury-induced ectopic nervedischarge in a model system of chronic pain utilizing injured nerve(Wall et al. (Eds), 1995, Textbook of Pain, Third Edition, Publ.,Churchill Livingston, pages 94-98; Devol et al., 1991, A Group Report:Mechanisms of neuropathic pain following peripheral injury. In: BasbaumeA I, et al (eds). TOWARDS A NEW PHARMACOTHERAPY OF PAIN, DahlemKonferenzen, Wiley, Chichester pp 417-440; Devor et al., 1985, Pain,22:127-137 at 128 and Devor, 1983, Pain 16:73-86). It has been reportedin one study that colchicine was given for the treatment of low-backpain, although oral colchicine has been shown to be ineffective for thesame indication (Schnebel et al., 1988, Spine 13(3):354-7). However, ithas not heretofore been known to use colchicine to prolong localanesthesia.

Thus, it has not previously been known to combine or otherwiseadminister both a controlled release local anesthetic and anon-glucocorticosteroid agent for augmenting the duration of localanesthesia.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a biodegradablecontrolled release dosage form for providing prolonged local anesthetictreatment of localized areas in humans and animals. More particularly,it is an object of the invention to provide a local anesthetic in abiocompatible, biodegradable controlled release form which provides aprolonged local anesthesia.

It is a further object of the present invention to provide a method forprolonging the effect of a local anesthetic agent at a desired site oftreatment which is safe, effective, and which effectively controlspost-operative pain.

It is a still further object to prolong the duration of the localanesthesia produced by administering an augmenting agent, before, duringor after administration of a local anesthetic according to theinvention, to a topical site or after infiltration, injection orimplantation of the compositions according to the invention.

In accordance with the above-mentioned objects and others, the inventionis related to biodegradable and/or bioerodable controlled releaseformulations for the administration of a local anesthetic agent capableof providing a prolonged effect in vivo, in combination with apharmaceutically acceptable augmenting agent which is effective toprolong the duration of the local anesthetic effect for a time periodgreater than that possible by the use of the local anesthetic incontrolled release form by itself (without the augmenting agent) andmethods for the manufacture thereof are disclosed. The controlledrelease formulation can be formed into slabs, rods, pellets,microparticles, (e.g., microspheres, microcapsules), spheroids andpastes. Preferably, the formulation is in a form suitable for suspensionin isotonic saline, physiological buffer or other solution acceptablefor injection into a patient.

The invention further provides methods for inducing localized anesthesiaby implanting, inserting or injecting a controlled release formulation,e.g., in the form of injectable microspheres loaded with a localanesthetic in sustained release form, into a site at or adjacent to anerve or nerves innervating a body region to provide local anesthesia.Thus, the controlled release formulation according to the invention mustbe applied, injected, infiltrated or implanted at a site in a patientwhere the local anesthetic agent is to be released.

Further aspects of the invention are directed to a method of treating apatient in need of a surgical procedure, comprising placing a localanesthetic in controlled release form in proximity to a nerve or nervesat a site to be anesthetized, e.g., a surgical site, and previously,simultaneously and/or subsequently administering the aforementionedaugmenting agent to substantially the same site to attain a prolongationof local anesthesia otherwise unattainable via the use of the localanesthetic alone.

The invention also provides for a unit dosage of the controlled releaseformulation comprising, in a container, a sufficient amount of theformulation to induce and/or prolong local anesthesia in at least onepatient. In one embodiment, the unit dosages are sterile andlyophilized. Alternatively, the unit dosages are sterile and prepared asa suspension in a solution acceptable for injection into a patient.

The invention is further directed in part to novel formulations forproviding local anesthesia, comprising a pharmaceutically-acceptablelocal anesthetic agent or a mixture of multiple different localanesthetic agents, in controlled release form, said formulation beingcapable of being placed in proximity to a nerve which is to beanesthetized, and an effective amount of a augmenting agent capable ofprolonging the localized anesthetic effect provided by the localanesthetic in controlled release form. The augmenting agent may beincorporated with the local anesthetic in controlled release form, oralternatively, at least part of the dose of the augmenting agent may beadministered separately but in proximity to the same location as thelocal anesthetic. At least a part of such a separate dose may beadministered later in time than the local anesthetic, to provideadditional augmentation of the extent and/or duration of the localanesthetic effect. A portion of the local anesthetic can be administeredto the desired site in immediate release form as long as a portion ofthe local anesthetic is also administered in controlled release form. Onthe other hand, the augmenting agent can be administered tosubstantially the same site at the same time as the local anesthetic, ata later time than the local anesthetic, or both, so long as the nerveblockade effect of the local anesthetic is substantially prolonged ascompared to that which would be obtained with the local anestheticalone.

In certain preferred embodiments of the invention, the local anestheticis prepared in matrices of biodegradable controlled release injectablemicrospheres. Optionally, the augmenting agent is incorporated intothese matrices along with the local anesthetic.

In further embodiments, the invention is directed to a suspensioncomprising a plurality of biocompatible, biodegradable controlledrelease microspheres comprising a local anesthetic agent, together withan augmenting agent which is incorporated in the controlled releasemicrospheres, or dissolved or suspended in the suspension ofmicrospheres. The suspension is, for example, suitable for administeringthe microspheres by injection.

In yet additional embodiments of the present invention, the localanesthetic is incorporated into a controlled release matrix having theaugmenting agent coated on the surface thereof.

In yet additional embodiments of the invention, the formulationcomprises a local anesthetic core; an augmenting agent present in thecore in an amount effective to prolong the effect of the localanesthetic in an environment of use, and a biocompatible, biodegradablecoating on the core providing a slow release of the local anestheticand/or augmenting agent in an environment of use.

In further embodiments, a portion or all of the local anesthetic isincorporated onto an outer surface of the coated substrate and a portionor all of the augmenting agent is optionally incorporated in the core,so that, e.g., augmenting agent continues to be released after the localanesthetic has dispersed from the controlled release material.

Where the local anesthetic is applied topically to epidermal and/ormucosal surfaces, the augmenting agent may also be topically appliedbefore, after or simultaneously with the local anesthetic.

The augmenting agent may be systemically administered by injection orinfiltration, instillation, oral dosing or other method to obtain thedesired prolongation of effect. Systemic administration, (e.g., oral orintravenous) while effective, will require a higher total dose of anaugmentation agent than with local administration in proximity to thelocal anesthetic.

The controlled release local anesthetic dosage form may be injected orinfiltrated, with or without an augmenting agent, at the site where theanesthetic is to be released. This can be prior to surgery, at the timeof surgery, or following removal (discontinuation) or reversal of asystemic anesthetic.

In one preferred embodiment, the formulation is prepared in the form ofmicrospheres. The microspheres may be prepared as a homogenous matrix ofa local anesthetic with a biodegradable controlled release material,with the augmenting agent optionally incorporated therein. Themicrospheres are preferably prepared in sizes suitable for infiltrationand/or injection, and injected at the site where the anesthetic is to bereleased before surgery, during the time of surgery, or followingremoval or reversal of systemic anesthetic.

Augmenting agents according to the present invention arepharmaceutically acceptable agents and include, for example,alkalinizing agents, non-glucocorticoid steroids such as neuroactivesteroids, modulators of gamma amino butyric acid receptors, modulatorsof ionic transport across cell membranes, antipyretic agents, adrenergicreceptor agonists or antagonists, tubulin binding agents, osmoticpolysaccharides, agonists and antagonists of potassium ATP channels, Na,K-ATPase inhibitors and enhancers, neurokinin antagonists,phosphatidylinositol-specific phospholipase C (“PLC”) inhibitors,inhibitors of leukocyte glucose metabolism, anti-convulsants,analeptics, a tranquilizing agent, antidepressant, an convulsant,leukotriene and prostaglandin agonists and inhibitors, phosphodiesteraseagonists and inhibitors, vasoconstrictive agents in sustained releaseform and combinations of any of the foregoing.

Examples demonstrate prolongation of the duration of local anesthesiawith the greater prolongation being provided by the combination of alocal anesthetic with a non-glucocorticoid augmenting agent.

DETAILED DESCRIPTION

Accordingly, the present invention provides for pharmaceuticallyacceptable augmenting agent or agents in conjunction with a localanesthetic in controlled release form that significantly increases thetime period of local anesthesia when administered at a site in apatient. The augmentation of efficacy provided by the use of theaugmenting agent cannot be predicted based on in vitro release(dissolution) of the local anesthetic in controlled release form: theinclusion of the augmenting agent within the controlled releaseformulations of the invention does not substantially alter or prolongthe in vitro dissolution rate of the local anesthetic agent from theformulation; yet, the same formulation when administered in vivoprovides a significant increase in the time period of local anesthesiaat the site of administration. The augmenting agents disclosed hereinare non-glucocorticoid agent and can be administered prior to, alongwith, or after administration, e.g., application, infiltration and/orinjection of the local anesthetic agent in controlled release form, ineach case with a substantial prolongation of local anesthesia in vivo.

The augmenting agent can be compounded in the same controlled releaseformulation as a local anesthetic agent or agents, in a separatecontrolled release formulation, e.g., different injectable microspheres,or in a non-controlled release, i.e., immediate release formulation. Theaugmenting agent may be administered before, simultaneously with, orafter injection or infiltration, implantation or insertion of thecontrolled release local anesthetic formulation at the desired site.

In those embodiments of the invention directed to formulations where theaugmenting agent is included in the formulation with the localanesthetic, the augmenting agent may be included in controlled releaseform or in immediate release form. The augmenting agent may beincorporated into any pharmaceutically acceptable carrier and preferablya carrier providing controlled release, including, e.g., a controlledrelease matrix along with the local anesthetic; incorporated into acontrolled release coating on a controlled release device orformulation; or incorporated as an immediate release layer coating thelocal anesthetic formulation. On the other hand, the augmenting agentmay be incorporated into a pharmaceutically acceptable aqueous mediumsuitable for infiltration or injection, either in controlled releaseform or in immediate release form.

Definitions

The controlled release formulations and methods of the invention may beused in conjunction with any system for application, infiltration,implantation, insertion, or injection known in the art, including butnot limited to microparticles, e.g., microspheres or microcapsules,gels, pastes, implantable rods, pellets, plates or fibers, and the like(generically referred to as “substrates”).

As used herein, the terms, “sustained release” and “controlled release”are well understood in the art and are intended to be interchangeable.

As used herein, the terms “local anesthetic agent” or “local anesthetic”means any drug which provides local numbness and/or analgesia. The termalso includes, but is not limited to, any drug which, when locallyadministered, e.g., topically or by infiltration or injection, provideslocalized full or partial inhibition of sensory perception and/or motorfunction. Under either definition, the localized condition so induced isalso referred to herein as “local anesthesia”. Local anesthetic agentswhich can be used include, simply by way of example, bupivacaine,ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine,mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, as wellas anesthetically active derivatives, analogs and mixtures thereof. Thelocal anesthetic can be in the form of a salt, for example, thehydrochloride, bromide, acetate, citrate, carbonate or sulfate. Morepreferably, the local anesthetic agent is in the form of a free base.The free base provides a slower initial release and avoids an early“dumping” of the local anesthetic at the injection site. Preferred localanesthetic agents include, e.g., bupivacaine. Local anesthetic agentstypically administered systematically may also be used in those caseswhere the means of administration results only in a local effect, ratherthan systemic. The term “local anesthetic” may also encompass, pursuantto the definitions provided herein, a drug of a different class thanthose traditionally associated with local anesthetic properties,including but not limited to morpline, fentanyl, and agents which, forexample, can provide regional blockade of nociceptive pathways (afferentand/or efferent).

As used herein, the term “patient” broadly refers to any animal that isto be treated with the compositions and by the methods herein disclosed.The disclosed local anesthetic dosage form can provide localized painblockade to any animal, e.g., any vertebrate, which it is desired to soanesthetize. In particular, the disclosed methods and compositions willfind use in veterinary practice and animal husbandry for, e.g., birdsand mammals, wherever prolonged local anesthesia is convenient ordesirable. In a preferred embodiment, the term includes humans in needof or desiring prolonged local anesthesia.

Augmenting Agents

Augmenting agents according to the invention are compositions orcompounds that prolong the duration of local anesthesia and/or enhancethe effectiveness of local anesthetic agents when delivered to the siteof local anesthetic administration before, simultaneously with or afterthe local anesthetic is administered. The augmenting agents are notglucocorticosteroid agents.

In one embodiment, the augmenting agents include an alkalinizing agent.The alkalinizing augmenting agents used herein preferably raise the pHof the medium in which the local anesthetic agents in controlled releaseform are present (e.g., either an injection medium or the environment atthe site of injection) to provide a pH from about 6.0 to about 8.5,preferably from about 7.5 to about 8.5. Preferably, the alkalinizingagent may be, for example, a carbonate buffer such as sodium carbonate.Of course, any other alkalinizing agent that is pharmaceuticallyacceptable for localized injection or infiltration may also beeffectively employed.

The augmenting agents also include non-glucocorticoid steroids such ase.g., androgens, such as testosterone and its active derivatives,analogs and metabolites; estrogens, such as estradiol and its activederivatives, analogs and metabolites and progestins, such asprogesterone and its active derivatives, analogs and metabolites andmixtures of any of these.

In another embodiment, the augmenting agents are neuroactive steroids,such as, e.g., one or more of the class of anesthetic steroids.Neuroactive steroids useful as augmenting agents according to theinvention also include those which modulate GABA receptors. Preferredneuroactive steroids include, simply by way of example, althesin and itsmain component, alphaxalone and active analogs, derivatives and mixturesthereof, as well as 5-alpha-pregnane-3 alpha-21 -diol-20-one(tetrahydro-deoxycorticosterone or THDOC) and/or allotetrahydrocortisone(the 17-beta configuration); and dehydroepiandrosterone (“DUE”) andactive analogs, derivatives and mixtures thereof. Preferably, theneuroactive steroids are present as an additive in the vehicle carryingthe microspheres in a concentration ranging from about 0.01 to about 1percent by weight, and most preferably from about 0.05 to about 0.5percent by weight.

The augmenting agents also include non-steroidal modulators of GABAreceptors, including those that are capable of potentiating theinhibitory effects of GABA on those receptors. Preferably, these includethe benzodiapenes, e.g., diazepam as well as its active derivatives,analogs and metabolites and mixtures thereof. More preferably, thediazepam is present as an additive in the vehicle in a concentrationranging from about 0.01 to about 1 percent by weight, and mostpreferably from about 0.05 to about 0.5 percent by weight. Of course,the artisan will appreciate that the potency of benzodiazapenes varieswidely, and will adjust these concentration ranges accordingly for otherbenzoldiazapenes, relative to the potency of diazepam.

In yet another aspect of the invention, the augmenting agent is amodulator of ionic transport across cell membranes. Monovalent andmultivalent metal ion transport can be modulated. Agents include, e.g.,sodium, potassium and calcium channel modulators (e.g., nifedipine,nitrendipine, verapamil, etc.). In preferred embodiments, these alsoinclude, but are not limited to, aminopyridine, benzamil, diazoxide, 5,5diphenylhydantoin, minoxidil, tetrethylammonium and valproic acid.Preferably, the ion transport modulating agent is present as an additivein the vehicle carrying the microspheres in a concentration ranging fromabout 0.01 to about 5 percent by weight, and most preferably from about0.05 to about 1.5 percent by weight.

Augmenting agents also include, e.g., antipyretic agents such asaminopyrine, phenazone, dipyrone, apazone, phenylbutazone andderivatives and analogs thereof Aminopyrine is preferably included inthe vehicle containing the microspheres in a concentration ranging fromabout 0.01 to about 0.5 percent and in a more preferred embodiment theconcentration ranges from about 0.05 to about 0.5 percent, by weight.

Other preferred augmenting agents include, e.g., adrenergic receptormodulators, such as α2 receptor agonists, can also be used as augmentingagents. Simply by way of example, the α2 receptor agonist clonidineprovides useful augmentation of local anesthesia, although any other artknown α2 receptor modulators capable of augmenting local anesthesiaaccording to the invention may be used. Clonidine is preferably includedin the vehicle containing the microspheres in a concentration rangingfrom about 0.01 to about 0.5 percent and in a more preferred embodimentthe concentration ranges from about 0.05 to about 1.0 percent, byweight.

Tubulin binding agents that are capable of promoting the formation ordisruption of cytoplasmic microtubules may be employed as augmentingagents according to the invention. Such agents include, for example,taxol, colchicine and the vinca alkaloids (vincristine and vinbiastine)as well as active derivatives, analogs metabolites and mixtures thereof.Of course, some agents may be classified in more than one category,thus, for example, colchicine is also known to inhibit glucosemetabolism in leukocytes. Coichicine is preferably included in thevehicle containing the microspheres in a concentration ranging fromabout 0.01 to about 1.0 percent and in a more preferred embodiment theconcentration ranges from about 0.05 to about 0.5 percent, by weight.

Osmotic polysaccharides are also able to be used as augmenting agents.In a one preferred embodiment, the osmotic polysaccharide includesdextran. More preferably, the dextran augmenting agents according to theinvention have a molecular weight ranging from 20 kDa through 200 kDa,or greater. A solution containing dextran in a form suitable forinjection or infiltration into a desired site in a patient is preferablybuffered to a pH ranging from 3.0 to 8.5, but in a preferred aspect isbuffered to a pH ranging from 7.0 to 8.5.

Other preferred embodiments of the invention provide for potassium-ATPchannel agonists for use as augmenting agents. A preferred potassium-ATPchannel agonist is, e.g., diazoxide, as well as its active derivatives,analogs, metabolites and mixtures thereof are usefull as augmentingagents.

Sodium/potassium ATPase inhibitors are also preferred as augmentingagents according to the invention. Preferably, the sodium/potassiumATPase inhibitors are cardiac glycosides that are effective to augmentlocal anesthesia. Cardiac glycosides that are useful according to theinvention include, e.g., oubaine, digoxin, digitoxin and activederivatives, analogs and metabolites and mixtures of any of these.

Additionally, augmenting agents according to the invention include,e.g., neurokinin antagonists, such as, e.g., spantide and other peptideinhibitors of substance P receptors that are well known to the art,e.g., as are listed in Receptor and Ion Channel Nomenclature Supplement,Trends in Pharmacological Sciences 18:64-65, the disclosure of which isincorporated by reference herein in its entirety. PLC inhibitors suchas, e.g., 1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-triene-17-yl]amino]hexl]-1-H-pyrrole-2,5-dione, and anti-seizure agents and agentsthat stabilize cell membrane potential, such as, e.g., benzodiazepines,barbiturates, deoxybarbiturates, carbamazepine, succinamides, valproicacid, oxazalidienbiones, phenacemide and active derivatives, analogs andmetabolites and mixtures thereof. Preferably, the anti-seizureaugmenting agent is phenytoin, and most preferably is5,5-diphenylhydantoin.

Surprisingly, locally acting vasoconstrictive agents, also provideeffective augmentation of local anesthesia that is unexpectedly superiorto that provided by immediate release vasoconstrictive agents. While notwishing to be bound by any hypothesis as to how vasconstrictive agentsin sustained release form might greatly prolong local anestheticactivity, it is believed that sustained release vasoconstrictor agentsprovide a controlled and non-toxic vasoconstrictor activity that reducesthe rate of local anesthetic washout from the treated tissue area toprolong the presence of effective concentrations of local anesthetic inthe tissue. It is known to the art that vasoconstrictors, e.g.,epinephrine, prolong local anesthetic activity for, at best, about 1hour and that if excessive amounts of epinephrine or othervasoconstrictor is administered in an attempt to further prolong localanesthesia, local circulation may be so disrupted as to cause tissuenecrosis and gangrene.

Surprisingly, controlled release vasoconstrictor agents can achievelocal tissue concentrations that are safe and effective to providevasoconstrictor activity effective to substantially prolong localanesthesia. More surprisingly, the local circulatory bed, i.e., bloodvessels, remain responsive to the vasoconstrictor agent for prolongedperiods, e.g., receptor desensitization or smooth muscle fatigue ortolerance does not prevent the prolongation effect. The gradual releasefrom a sustained release formulation also serves to greatly reduce therisk of toxic reactions such as, e.g., localized tissue necroses

As for the previously discussed augmenting agents, vasoconstrictiveaugmenting agents can be administered before, simultaneously with orafter the administration of local anesthetic. In one embodiment of theinvention, at least a portion of the vasoconstrictive agent isformulated in a sustained release formulation together with localanesthetic. In another embodiment, the vasconstrictive agent is preparedin one or separate sustained release formulations. It will beappreciated that by manipulating the loading of, e.g., microspherescontaining vasoconstrictor agent, the artisan can determine the numberof microspheres necessary to administer a given dose. Thus, simply byway of example, microspheres loaded with about 75 percent by weight ofvasoconstrictor agent will require half of the microspheres necessary toadminister a predetermined dose than will microspheres loaded with about45 percent by weight of vasoconstrictor agent.

Vasoconstrictor agents can formulated into, e.g., sustained releasemicrospheres including both a local anesthetic, e.g., bupivacaine freebase, and a vasoconstrictor agent. Vasoconstrictor agents can also beformulated into, e.g., sustained release microspheres including localanesthetic without a vasoconstrictive agent.

In one embodiment, local anesthetic and vasoconstrictor agents areadministered simultaneously in the form of, e.g., separate microspheressuspended in a single medium suitable for injection or infiltration, orin separate microspheres suitable for injection, e.g., at the same site.In a Further embodiment, simply by way of example, administration ofsustained release microspheres with combined local anesthetic andvasoconstrictor agent can also be followed by one or more additionaladministrations of such combination formulation and/or of microspheresincluding as the active agent only local anesthetic or onlyvasoconstrictor agent. Augmenting agents that are vasoconstrictor agentsin sustained release form include, but are not limited to,catecholamines e.g., epinephrine, norepinephrine and dopamine as wellas, e.g., metaraminol, phenylephrine, methoxamine, mephentermine,methysergide, ergotamine, ergotoxine, dihydroergotamine, sumatriptan andanalogs, and alpha-1 and alpha-2 adrenergic agonists, such as, e.g.,clonidine, guanfacine, guanabenz and dopa (i.e.,dihyrdoxyphenylalanine), methyldopa, ephedrine, amphetamine,methamphetamine, methylphenidate, ethylnorepinephrine ritalin, pemolineand other sympathomimetic agents, including active metabolites,derivatives and mixtures of any of the foregoing.

In a more preferred embodiment, at least a portion of any of theaugmenting agents enumerated above are included in the controlledrelease formulation, in combination with a local anesthetic agent oragents in a concentration ranging from about 0.01 to about 30 percent ormore, by weight, relative to the weight of the formulation.

The artisan will also appreciate that other augmenting agents accordingto the invention broadly include any other types and classifications ofdrugs or active agents known to the art. Such augmenting agents arereadily identified by routine screening as discussed hereinbelow usinganimal sensory and motor quantitation protocols well known to the art.

A local anesthetic according to the invention can also be formulated,e.g., in injectable microspheres, in combination with at least onevasoconstrictor augmenting agent according to the invention. In oneembodiment, the vasoconstrictor can be included in the vehicle suitablefor injection carrying the microspheres. In a further embodiment, atleast a portion of the vasoconstrictor can also be formulated into asustained release formulation, e.g., injectable microspheres, togetherwith the local anesthetic. In a still further embodiment, at least aportion of the vasoconstrictor can be prepared in a separate sustainedrelease formulation.

The vasoconstrictor can be included in either a single or combinationformulation in an amount ranging from about 0.001 percent to about 90percent, by weight relative to the total weight of the formulation.Preferably, the vasoconstrictor is included in a controlled releaseformulation in an amount ranging from about 0.005 percent to about 20%,and more preferably, from about 0.05 percent to about 5 percent, byweight, relative to the total weight of the formulation. When avasoconstrictor is present in the injection vehicle in immediate releaseform, it is present in amounts ranging from about 0.01% to about 5percent, or more, by weight, relative to the injection vehicle. Thevasoconstrictor can also be provided in a ratio of local anesthetic,e.g., bupivacaine to vasoconstrictor, ranging from about 10:1 to about20,000 and preferably from about 100:1 to about 2000:1 and from about500:1 to about 1500:1.

Of course, the artisan will appreciate that the amounts of augmentingagent and local anesthetic will vary depending upon the relative potencyof the agents selected, the depth and duration of local anesthesiadesired.

Of course, the artisan will appreciate that the optimal concentrationand/or quantities or amounts of any particular augmenting agent, whetherpresent in the injection vehicle, separately administered before, duringor after local anesthesia is induced or whether included in themicrosphere formulation, may be adjusted to accommodate variations inthe treatment parameters. Such treatment parameters include the polymercomposition of a particular microsphere preparation, the particularlocal anesthetic utilized, and the clinical use to which the preparationis put, in terms of the site treated for local anesthesia, the type ofpatient, e.g., human or non-human, adult or child, and the type ofsensory stimulus to be anesthetized.

Further, the concentration and/or amount of any particular augmentingagent for a given formulation may readily identified by routinescreening in animals, e.g., rats, by screening a range of concentrationand/or amounts of augmenting agent using the hotplate foot withdrawalassay and/or motor function assay described hereinbelow. Art knownmethods are also available to assay local tissue concentrations,diffusion rates from microspheres and local blood flow before and afteradministration of local anesthetic formulations according to theinvention. One such method is microdialysis, as reviewed by T. E.Robinson et al., 1991, MICRODIALYSIS IN THE NEUROSCIENCES, Techniques,volume 7, Chapter 1, pages 1-64. The methods reviewed by Robinson can beapplied, in brief, as follows. A microdialysis loop is placed in situ ina test animal. Dialysis fluid is pumped through the loop. Whenmicrospheres according to the invention are injected adjacent to theloop, released drugs, e.g., bupivacaine and vasoconstrictor augmentingagents, are collected in the dialysate in proportion to their localtissue concentrations. The progress of diffusion of the active agentscan be determined thereby with suitable calibration procedures usingknown concentrations of active agents. For the vasoconstrictoraugmenting agents, decrements and durations of vasoconstriction effectscan be measured by clearance rates of marker substances, e.g., methyleneblue or radiolabeled albumen from the local tissue from themicrospheres, as well as the local blood flow

The optimal concentration of augmenting agent for human clinical use mayalso be readily determined by routine animal screening as describedhereinbelow, and further adjusted, where indicated, by routine clinicalexperience.

Formulations

Any pharmaceutically acceptable carrier vehicle or formulation suitablefor local implantation, infiltration or injection in proximity to anerve that is able to provide a controlled release of a local anestheticagent and/or augmenting agent may be employed to provide for prolongedlocal anesthesia as needed. Slow release formulations known in the artinclude specially coated pellets, polymer formulations or matrices forsurgical insertion or as controlled release microparticles, e.g.,microspheres or microcapsules, for implantation, insertion or injection,wherein the slow release of the active medicament is brought aboutthrough controlled diffusion out of the matrix and/or selectivebreakdown of the coating of the preparation or selective breakdown of apolymer matrix. Other formulations or vehicles for controlled orimmediate delivery of an agent to a preferred localized site in apatient include, e.g., suspensions, emulsions, liposomes and any othersuitable, art known, delivery vehicle or formulation.

In a preferred embodiment, the slow release formulation is prepared asmicrospheres in a size distribution range suitable for localinfiltration or injection. The diameter and shape of the microspheres orother particles can be manipulated to modify the releasecharacteristics. For example, larger diameter microspheres willtypically provide slower rates of release and reduced tissue penetrationand smaller diameters of microspheres will produce the opposite effects,relative to microspheres of different mean diameter but of the samecomposition. In addition, other particle shapes, such as, for example,cylindrical shapes, can also modify release rates by virtue of theincreased ratio of surface area to mass inherent to such alternativegeometrical shapes, relative to a spherical shape. The diameter ofinjectable microspheres are in a size range from, for example, fromabout 5 microns to about 200 microns in diameter. In a more preferredembodiment, the microspheres range in diameter from about 20 to about120 microns.

A wide variety of biodegradable materials may be utilized to provide thecontrolled release of the local anesthetic. Any pharmaceuticallyacceptable biodegradable polymers known to those skilled in the art maybe utilized. It is preferred that the biodegradable controlled releasematerial degrade in vivo over a period of less than about two years,with at least 50% of the controlled release material degrading withinabout one year, and more preferably six months or less. More preferably,the controlled release material will degrade significantly within one tothree months, with at least 50% of the material degrading into non-toxicresidues which are removed by the body, and 100% of the drug beingreleased within a time period from about two weeks to about two months.The controlled release material should preferably degrade by hydrolysis,and most preferably by surface erosion, rather than by bulk erosion, sothat release is not only sustained but also provides desirable releaserates. However, the pharmacokinetic release profile of theseformulations may be first order, zero order, bi- or multi-phasic, toprovide the desired reversible local anesthetic effect over the desiredtime period.

The controlled release material should be biocompatible. In the case ofpolymeric materials, biocompatibility is enhanced by recrystallizationof either the monomers forming the polymer and/or the polymer usingstandard techniques.

Suitable biodegradable polymers can be utilized as the controlledrelease material. The polymeric material may comprise a polylactide, apolyglycolide, a poly(lactide-co-glycolide), a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, soluble derivatives of polysaccharides, solublederivatives of proteinaceous polymers, polypeptides, polyesters, andpolyorthoesters or mixtures or blends of any of these. Thepolysaccharides may be poly-1,4-glucans, e.g., starch glycogen, amylose,amylopectin, and mixtures thereof. The biodegradable hydrophilic orhydrophobic polymer may be a water-soluble derivative of apoly-1,4-glucan, including hydrolyzed amylopectin, hydroxyalkylderivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES),hydroxyethyl amylose, dialdehyde starch, and the like. Preferredcontrolled release materials which are useful in the formulations of theinvention include the polyanhydrides, co-polymers of lactic acid andglycolic acid wherein the weight ratio of lactic acid to glycolic acidis no more than 4:1 (i.e., 80% or less lactic acid to 20% or moreglycolic acid by weight), and polyorthoesters containing a catalyst ordegradation enhancing compound, for example, containing at least 1% byweight anhydride catalyst such as maleic anhydride. Other usefulpolymers include protein polymers such as gelatin and fibrin andpolysaccharides such as hyaluronic acid. Since polylactic acid takes atleast one year to degrade in vivo, this polymer should be utilized byitself only in circumstances where such a degradation rate is desirableor acceptable.

The polymeric material may be prepared by any method known to thoseskilled in the art. For example, where the polymeric material iscomprised of a copolymer of lactic and glycolic acid, this copolymer maybe prepared by the procedure set forth in U.S. Pat. No. 4,293,539(Ludwig, et al.), the disclosure of which is hereby incorporated byreference in its entirety. In brief, Ludwig prepares such copolymers bycondensation of lactic acid and glycolic acid in the presence of areadily removable polymerization catalyst (e.g., a strong acidion-exchange resin such as Dowex HCR-W2-H). The amount of catalyst isnot critical to the polymerization, but typically is from about 0.01 toabout 20 parts by weight relative to the total weight of combined lacticacid and glycolic acid. The polymerization reaction may be conductedwithout solvents at a temperature from about 100° C. to about 250° C.for about 48 to about 96 hours, preferably under a reduced pressure tofacilitate removal of water and by-products. The copolymer is thenrecovered by filtering the molten reaction mixture to removesubstantially all of the catalyst, or by cooling and then dissolving thereaction mixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.

Pharmaceutically acceptable polyanhydrides which are useful in thepresent invention have a water-labile anhydride linkage. The rate ofdrug release can be controlled by the particular polyanhydride polymerutilized and its molecular weight. The polyanhydride polymer may bebranched or linear. Examples of polymers which are useful in the presentinvention include homopolymers and copolymers of poly(lactic acid)and/or poly(glycolic acid), poly[bis(p-carboxyphenoxy)propane anhydride](PCPM), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides ofoligomerized unsaturated aliphatic acids, polyanhydride polymersprepared from amino acids which are modified to include an additionalcarboxylic acid, aromatic polyanhydride compositions, and co-polymers ofpolyanhydrides with other substances, such as fatty acid terminatedpolyanhydrides, e.g., polyanhydrides polymerized from monomers of dimersand/or trimers of unsaturated fatty acids or unsaturated aliphaticacids. Polyanhydrides may be prepared in accordance with the methods setforth in U.S. Pat. No. 4,757,128, hereby incorporated by reference. Forexample, polyanhydrides may be synthesized by melt polycondensation ofhighly pure dicarboxylic acid monomers converted to the mixed anhydrideby reflux in acetic anhydride, isolation and purification of theisolated prepolymers by recrystallization, and melt polymerization underlow pressure (10⁻⁴ mm) with a dry ice/acetone trap at a temperaturebetween 140°-250° C. for 10-300 minutes. High molecular weightpolyanhydrides are obtained by inclusion of a catalyst which increasesthe rate of anhydride interchain exchange, for example, alkaline earthmetal oxides such as CaO, BaO and CACO₃. Polyorthoester polymers may beprepared, e.g., as set forth in U.S. Pat. No. 4,070,347, herebyincorporated by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers andtheir soluble derivatives include gelation biodegradable syntheticpolypeptides, elastin, alkylated collagen, alkylated elastin, and thelike. Biodegradable synthetic polypeptides includepoly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine,copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutaminewith other amino acids. Suggested amino acids include L-alamine,L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In embodiments where the biodegradable polymer comprises a gel, one suchuseful polymer is a thermally gelling polymer, e.g., polyethylene oxide,polypropylene oxide (PEO-PPO) block copolymer such as Pluronic® F127from BASF Wyandotte. In such cases, the local anesthetic formulation maybe injected via syringe as a free-flowing liquid, which gels rapidlyabove 30° C. (e.g., when injected into a patient). The gel system thenreleases a steady dose of local anesthetic at the site ofadministration.

In additional embodiments, the controlled release material, which ineffect acts as a carrier for the local anesthetic and/or the augmentingagent, can further include a bioadhesive polymer such as pectins(polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) ornon-toxic lectins or the polymer itself may be bioadhesive, e.g.,polyanhydride or polysaccharides such as chitosan.

Definitions or further descriptions of any of the foregoing terminologyare well known in the art and may be found by referring to any standardbiochemistry reference text such as “Biochemistry” by Albert L.Lehninger, Worth Publishers, Inc. and “Biochemistry” by Lubert Stryer,W.H. Freeman and Company, both of which are hereby incorporated byreference.

The aforementioned biodegradable hydrophobic and hydrophilic polymersare particularly suited for the methods and compositions of the presentinvention by reason of their characteristically low human toxicity andvirtually complete biodegradability.

The substrates of the presently described formulations in certainpreferred embodiments are manufactured using a method that evenlydisperses the local anesthetic throughout the formulation, such asemulsion preparation, solvent casting, spray drying or hot melt, ratherthan a method such as compression molding. A desired release profile canbe achieved by using a mixture of polymers having different releaserates and/or different percent loading of local anesthetic and/oraugmenting agent, for example, polymers releasing in one day, threedays, and one week. In addition, a mixture of microspheres having one ormore different local anesthetic agents, having the same or differentcontrolled release profile, can be utilized to provide the benefits ofdifferent potencies and spectrum of activity during the course oftreatment.

Methods for manufacture of microspheres are well known and are typifiedin the following examples. Examples of suitable methods of makingmicrospheres include solvent evaporation, phase separation and fluidizedbed coating.

In solvent evaporation procedures, the local anesthetic agent, ifsoluble in organic solvents, may be entrapped in the biodegradablepolymer by dissolving the polymer in a volatile organic solvent, addingthe drug to the organic phase, emulsifying the organic phase in waterwhich contains less than 2% polyvinyl alcohol, and finally removing thesolvent under vacuum to form discrete, hardened monolithic microspheres.

Phase separation microencapsulation procedures are suitable forentrapping water-soluble agents in the polymer to prepare microcapsulesand microspheres. Phase separation involves coacervation of the polymerfrom an organic solvent by addition of a nonsolvent such as siliconeoil. In a preferred embodiment, the microspheres may be prepared by theprocess of Ramstack et al., 1995, in published international patentapplication WO 95/13799, the disclosure of which is incorporated hereinin its entirety. The Ramstack et al. process essentially provides for afirst phase, including an active agent and a polymer, and a secondphase, that are pumped through a static mixer into a quench liquid toform microparticles containing the active agent. The first and secondphases can optionally be substantially immiscible and the second phaseis preferably free from solvents for the polymer and the active agentand includes an aqueous solution of an emulsifier.

In fluidized bed coating, the drug is dissolved in an organic solventalong with the polymer. The solution is then processed, e.g., through aWurster air suspension coating apparatus to form the final microcapsuleproduct.

The biodegradable controlled release materials may be used in order toprepare controlled release local anesthetic implants. The implants maybe manufactured, e.g., by compression molding, injection molding, andscrew extrusion, whereby the local anesthetic agent is loaded into thepolymer. Implantable fibers can be manufactured, e.g., by blending thelocal anesthetic agent with the controlled release material and thenextruding the mixture, e.g., under pressure, to thereby obtainbiodegradable fibers. In certain preferred embodiments, the augmentingagent may be incorporated into the implant, or may be coated onto asurface of the implant.

In other embodiments of the invention, the controlled release materialcomprises an artificial lipid vesicle, or liposome. The use of liposomesas drug delivery systems is known, and comprehensive review articles ontheir properties and clinical applications are available; see, e.g.,Barenholz and Amselem, in “Liposome Technology”, 2nd ed., G.Gregoriadis, ed., CRC Press, 1992; Lichtenberg and Barenholz, in Methodsfor Biochemical Analysis, 33, D. Glick, ed., 1988. A liposome is definedas a structure consisting of one or more concentric lipid bilayersseparated by water or aqueous buffer compartments. These hollowstructures, which have an internal aqueous compartment, can be preparedwith diameters ranging from 20 nm to 10 μm. They are classifiedaccording to their final size and preparation method as: SUV, smallunilamellar vesicles (0.5-50 nm); LUV, large unilamellar vesicles (100nm); REV, reverse phase evaporation vesicles (0.5 μm); and MLV, largemultilamellar vesicles (2-10 μm).

Liposomes as described herein will vary in size. Preferably, theliposomes have a diameter between 100 nm and 10 microns or greater. Awide variety of lipid materials may be used to form the liposomesincluding natural lecithins, e.g., those derived from egg and soya bean,and synthetic lecithins, the proviso being that it is preferred that thelipids are non-immunogenic and bio-degradable. Also, lipid-basedmaterials formed in combination with polymers may be used, such as thosedescribed in U.S. Pat. No. 5,188,837 to Domb, (incorporated by referenceherein).

Examples of synthetic lecithins which may be used together with theirrespective phase transition temperatures, aredi-(tetradecanoy)phosphatidylcholine (DTPC) (23° C.),di-(hexadecanoyl)phosphatidylcholine (DHPC) (41° C.) anddi-(octandecanoyl) phosphatidylcholine (DOPC) (55° C.).Di-(hexadecanoyl) phosphatidylcholine is preferred as the sole or majorlecithin, optionally together with a minor proportion of thedi-(octadecanoyl) or the di-(tetradecanoyl) compound. Other syntheticlecithins which may be used are unsaturated synthetic lecithins, forexample, di-(oleyl)phosphatidyl-choline anddi-(linoleyl)phosphatidylcholine. In addition to the mainliposome-forming lipid or lipids, which are usually phospholipids, otherlipids (e.g. in a proportion of 5-40% w/w of the total lipids) may beincluded, for example, cholesterol or cholesterol stearate, to modifythe structure of the liposome membrane, rendering it more fluid or morerigid depending on the nature of the main liposome-forming lipid orlipids.

In certain embodiments, the augmenting agent is incorporated along withthe local anesthetic agent into the lipid. In other preferredformulations, the lipids containing the local anesthetic agent aredispersed in a pharmaceutically acceptable aqueous medium. Theaugmenting agent may be incorporated into this aqueous medium. In afurther embodiment, a portion of the dose of the local anesthetic isincorporated into the aqueous medium in immediate release form. Theresultant formulation is an aqueous suspension which may comprise thelocal anesthetic and/or augmenting agent partitioned between a freeaqueous phase and a liposome phase.

As an even further alternate embodiment, liposomes containing localanesthetic may be combined in an aqueous phase where liposomescontaining the augmenting agent to form an aqueous pharmaceuticalsuspension useful for administration at the desired site in the patientto be anesthetized. This may be accomplished via injection orimplantation. Liposomes may be prepared by dissolving an appropriateamount of a phospholipid or mixture or phospholipids together with anyother desired lipid soluble components (e.g., cholesterol, cholesterolstearate) flowing in a suitable solvent (e.g., ethanol) and evaporatingto dryness. An aqueous solution of the local anesthetic, optionally withaugmenting agent, may then be added and mixed until a lipid film isdispersed. The resulting suspension will contain liposomes ranging insize, which may then fractionated to remove undesirable sizes, ifnecessary. This fractionation may be effected by column gelchromatography, centrifugation, ultracentrifugation or by dialysis, aswell known in the art.

The above method of preparation of liposomes is representative of apossible procedure only. Those skilled in the art will appreciate thatthere are many different methods of preparing liposomes, all of whichare deemed to be encompassed by the present disclosure.

In additional embodiments of the invention, the substrate comprises aplurality of microcapsules laden with the local anesthetic agent with orwithout the augmenting agent. Microcapsules may be prepared, forexample, by dissolving or dispersing the local anesthetic agent in anorganic solvent and dissolving a wall forming material (polystyrene,alkylcelluloses, polyesters, polysaccharides, polycarbonates,poly(meth)acrylic acid ester, cellulose acetate,hydroxypropylmethylcellulose phthalate, dibutylaminohydroxypropyl ether,polyvinyl butyral, polyvinyl formal, polyvinylacetal-diethylaminoacetate, 2-methyl-5-vinyl pyridine methacrylate-methacrylic acidcopolymer, polypropylene, vinylchloride-vinylacetate copolymer, glyceroldistearate, etc.) in the solvent; then dispersing the solvent containingthe local anesthetic agent and wall forming material in acontinuous-phase processing medium, and then evaporating a portion ofthe solvent to obtain microcapsules containing the local anestheticagent in suspension, and finally, extracting the remainder of thesolvent from the microcapsules. This procedure is described in moredetail in U.S. Pat. Nos. 4,389,330 and 4,530,840, hereby incorporated byreference.

The controlled release dosage forms of the present invention preferablyprovide a sustained action in the localized area to be treated. Forexample, it would be desirable that such a formulation provideslocalized anesthesia to the site for a period of one day, two days,three days, or longer. The formulations can therefore, of course, bemodified in order to obtain such a desired result.

Microspheres and other injectable substrates described herein may beincorporating an effective amount of the same into a pharmaceuticallyacceptable solution (e.g., water) or suspension for injection. The finalreconstituted product viscosity may be in a range suitable for the routeof administration. In certain instances, the final reconstituted productviscosity may be, e.g., about 35 cps. Administration may be via thesubcutaneous or intramuscular route. However, alternative routes arealso contemplated, and the formulations may be applied to the localizedsite in any manner known to those skilled in the art, such that alocalized effect is obtained. The substrate formulations of theinvention can be implanted at the site to be treated. Thereby, theformulations of the present invention, when including a localanesthetic, may be used in the control of post-operative pain.

The local anesthetic is incorporated into the polymer or othercontrolled-release formulation in a percent loading between 0.1% and 90%or more, by weight, preferably between 5% and 80%, or more, by weightand more preferably between 65 and 80%, or more, by weight. In an evenmore preferred embodiment, the local anesthetic is loaded at about 75%by weight.

It is possible to tailor a system to deliver a specified loading andsubsequent maintenance dose by manipulating the percent drugincorporated in the polymer and the shape of the matrix or formulation,in addition to the form of local anesthetic (e.g., free base versussalt) and the method of production. The amount of drug released per dayincreases proportionately with the percentage of drug incorporated intothe formulation, e.g., matrix (for example, from 5 to 10 to 20%). In thepreferred embodiment, polymer matrices or other formulations with about75% drug incorporated are utilized, although it is possible toincorporate substantially more drug, depending on the drug, the methodused for making and loading the device, and the polymer.

When the augmenting agent is included in the controlled releasesubstrates comprising local anesthetic, it has been found that usefullloadings of augmenting agent are from about 0.001% to about 30% byweight of the substrate or preferably from about 0.01% to about 5% byweight of the substrate. When the augmenting agent is included incontrolled release substrates without local anesthetic, it has beenfound that useful loadings of augmenting agent are from about 0.001percent to about 90%, or more, by weight of the substrate, or preferablyfrom about 0.001 to about 30% by weight of the substrate or morepreferably from about 0.01% to about 5% by weight of the substrate.

When the augmenting agent is included as part of the (aqueous) injectionmedium, the augmenting agent may be present in a weight percent relativeto the local anesthetic varying from about 0.01% to about 15%.

The dosage of the controlled release microsphere formulations isdependent upon the kind and amount of the drug to be administered, therecipient animal, and the objectives of the treatment. For example, whenthe local anesthetic included in the microspheres of the presentinvention is bupivacaine, the formulation may include, e.g., from about0.5 to about 2 mg/kg body weight. The effective dose of bupivacaine, oran amount of another local anesthetic sufficient to provide proportionalpotency, can range from about 1 to 50 mg of bupivacaine injected orinserted at each site where the release of a local anesthetic agent isdesired. In certain preferred embodiments, the dose of bupivacaine inthe controlled release dosage form of the invention is sufficient toprovide a controlled release of about 1 to 4 mg per day at the releasesite for at least 1 to 4 days. Since the formulations of the presentinvention are controlled release, it is contemplated that formulationsmay include much more than usual immediate release doses, e.g., as muchas 120 mg/kg bupivacaine or more.

In certain preferred embodiments, the controlled release substratecomprising local anesthetic and/or augmenting agent provides from about10 to about 60 percent release of drug, e.g., local anesthetic after 24hours, from about 20 to about 80 percent release after 48 hours and fromabout 40 to about 100 percent release after 72 hours. More preferably,the controlled release substrate comprising local anesthetic providesfrom about 25 to about 40 percent release of local anesthetic after 24hours, from about 40 to about 50 percent release after 24 hours and fromabout 45 to about 55 percent release after 72 hours and 80 to 100percent cumulative release is provided after about 280 hours.

In order to obtain a local anesthetic effect in vivo when combined withthe augmenting agent as described herein of at least about 40 hours theaugmenting agent is placed into approximately the same site in a patient(e.g., human or veterinary) before, simultaneously with, or after theplacement of a local anesthetic at that site. The presence of augmentingagent in the controlled release formulation does not significantlyaffect the in vitro release rates of local anesthetic.

In a preferred embodiment the local anesthetic effect is prolonged bythe use of an augmenting agent by at least about 15%, e.g., from about15% to about 1400% or more preferably from about 300% to about 1000percent or more and more preferably from about 300% to about 500%, ormore of the duration of the local anesthetic effect that is obtainedfrom the same formulation without benefit of an augmenting agent. Theduration of the local anesthetic effect prolonged by an augmenting agentranges from about 30 minutes to about 150 hours, or more, and preferablyfrom 1 hour to about 1 to about 24 hours or more, and more preferablyfrom about 1 hour to about 12 hours, or more.

The rate of release of local anesthetic agent or other drugsincorporated into the formulation will also depend on the solubilityproperties of the local anesthetic or drug. The greater the solubilityin water, the more rapid the rate of release in tissue, all otherparameters being unchanged. For example, those local anesthetic agentshaving pH dependent solubility will be released more rapidly at theoptimum pH for those compounds. Thus, the formulation may be optimizedfor the desired local anesthetic release rate by selecting localanesthetic agents having a desired water solubility in tissue, e.g., attissue pH. Thus, a local anesthetic agent that is more soluble at acidpH will have a faster release rate in a relatively acidic (e.g., pH lessthan about 7.2) tissue. For example, in one embodiment, the formulationwill have released, in vitro, at least 70 percent of a local anestheticat 48 hours at about pH 6 and will have released at least 40 percent ofa local anesthetic at a pH ranging from about 7.4 to about 8, at 48hours. Other combinations are pH independent in their release.

The examples demonstrate that the above-described augmenting agentsprolong the duration of local anesthesia in vivo and do notsignificantly alter the time course of release of bupivacaine in vitro.

Applications

Potential applications include any condition for which localized nerveblockade is desirable. This includes both local anesthesia for therelief of pain and motor symptoms as well as local anesthesia for othermedical purposes. The formulations and methods according to theinvention can be used to provide two to five day intercostal blockadefor thoracotomy, or longer term intercostal blockade for thoracicpost-therapeutic neuralgia, lumbar sympathetic blockade for reflexsympathetic dystrophy, or three-day ilioinguinal/iliohypogastricblockade for hernia repair. Other potential applications includeobstetrical or gynecological procedures. Yet further potentialapplications include providing localized temporary sympathectomy, e.g.,blockade of sympathetic or parasympathetic ganglia to treat a variety ofautonomic diseases, including circulatory dysfunction or cardiacdysrhythmias. The formulations may also be used to treat trigeminalneuralgia and other diseases of the cranial nerves as well as to providea temporary nerve block to treat localized muscle spasm and treatment ofretrobulbar conditions, e.g., eye pain. Other uses includeintra-operative administration in order to reduce pain during and afterthe operative procedure, especially for plastic surgery procedures whereprolonged local anesthesia will enhance the outcome. These systems canalso be used for the management of various forms of persistent pain,such as postoperative pain, sympathetically maintained pain, or certainforms of chronic pain such as the pain associated with many types ofcancer. These systems may also be used for blockade of nociceptivepathways (afferent and efferent) in patients with acute pancreatitis,ileus, or other visceral disorders. These are merely examples, andadditional uses for both human and veterinary practice are immediatelyapparent to the artisan.

Methods of Administration

In a preferred method of administration a dosage form, e.g.,microspheres, are administered by injection into a site where localanesthetic agent is to be released. Microspheres may be injected througha syringe or a trochar. Pellets or slabs may be surgically placed into asite where release of oral anesthetic agent is desired. Controlledrelease gels, pastes or suspensions, including gels, pastes orsuspension containing microspheres, may also be administered topicallyto a skin or mucosal surface of the body to obtain topical, localizedanesthesia.

As described below, microspheres according to the invention can beadministered alone or in combination with a solution including anon-glucocorticosteroid augmenting agent in an amount effective toprolong the duration of local anesthesia. Alternatively, themicrospheres include an amount of a non-glucocorticosteroid augmentagent effective to prolong the duration of local anesthesia.

In another alternative, one or more augmenting agents can beadministered before, simultaneously with or after administration of thecontrolled release local anesthetic, wherein the augmenting agent isformulated into a separate microsphere formulation for controlledrelease. The controlled release rate for the augmenting agents may bethe same as or different than the controlled release rate for the localanesthetic. The separate microsphere can be administered in a singleinjection, i.e., in a single injection vehicle, or in separateinjections simultaneously or at different times In a further embodiment,it has been found that additional dose of augmenting agent may also beadministered as an injectable solution, in an injectable carrier or in acontrolled release carrier to the nerve to be blockaded after thecontrolled release local anesthesia has worn off, in order to reactivatethe initial local anesthesia without the co-administration of additionallocal anesthetic.

The microspheres may be prepared from PLGA polymers ranging from, forexample, PLGA in a ratio of 50/50, 65/35 or 75/25. An optimumcomposition has been determined to be PLGA 65/35. The microspheres,formulated with, e.g., PLGA 65/35 microspheres are administered in adose ranging from, for example, 2 through 450 mg of microspheres 75%(w/w) loaded with a local anesthetic such as bupivacaine, per kg of thepatient to be treated. In a preferred embodiment the dose ranges from 5through 450 mg/kg. In a more preferred embodiment the dose ranges fromabout 10 to about 150 mg/kg with PLGA 65/35. Certainly, the artisan willappreciate the fact that the dose ranges mentioned above are based onthe potency of bupivacaine, and that exact effective dosages will varywith the particular relative potency and pharmacokinetics of each localanesthetic and will be able to readily adjust the dose according to thedegree of blockade experienced by the patient.

The use of the above-described augmenting agents before, simultaneouslywith or after administration of a controlled release local anesthesia,results in prolonged anesthesia.

The formulation described herein can also be used to administer localanesthetic agents that produce modality-specific blockade, as reportedby Schneider, et al., Anesthesiology, 74:270-281 (1991), or that possessphysical-chemical attributes that make them more useful for sustainedrelease then for single injection blockade, as reported by Masters, etal., Soc. Neurosci, Abstr., 18:200 (1992), the teachings of which areincorporated herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following non-limiting examples illustrate the preparation of theformulations according to the invention and the effects of localanesthetic and augmenting agents alone and in combination.

EXAMPLES 1-3 Solvent Extraction Process

In Examples 1-3, bupivacaine microspheres are prepared by dissolving thebupivacaine base and the polymer in ethyl acetate. The polymer is 50:50poly (D,L) lactic co-glycolic acid which has a mole percent compositionof 50% lactide and 50% glycolide. This dispersed phase is then added toa solution of polyvinyl alcohol (PVA) in water (the continuous phase)with stirring. The resulting emulsion is monitored for droplet size,which is in turn controlled by the rate of stirring. The emulsion isthen added to water to extract the solvent and to harden themicrospheres. The mixture is then filtered and the microspheres aredried under vacuum at room temperature. The desired particle sizefraction is then collected by sieving.

Each of Examples 1-3 are prepared such that the microspheres have arelatively high drug content. In Example 1, the theoretical drug contentis about 60%, and the size of the microspheres range from about 45 toabout 90 microns. In Example 2, the theoretical drug content is about61%, and the range in the size of the microspheres is from about 45 toabout 63 microns. In Example 3, the theoretical drug content is about65%, and the range in particle size of the microspheres is from about 45to about 63 microns.

The microspheres of Examples 1-3 are then suspended in a suitable mediafor injection, in this case water. Thereafter, the microspheres aresubjected to in-vitro dissolution testing. An automated dissolution testmethod is utilized using the USP/NF Paddle Method II. The dissolutionmedium is 900 ml of Tris buffer with 0.05% sodium dodecyl sulfate at pH7.4 at 37° C. with a stirring speed of about 50 RPM. The surfactant isadded in order to prevent the microspheres from floating on the surfaceof the dissolution medium. Further information concerning theseformulations is presented in Table 1 below.

TABLE 1 In vitro M-Sphere MW of Release Formu- Size Theoretical Actual50:50 24 72 lation Range % Drug % Drug dl-PLGA hrs hrs Ex. 1 45-90 μ 62%47% — 28% 68% Ex. 2 45-63 μ 61% 56% 50K 52% 91% Ex. 3 45-63 μ 65% 59%50K 22% 46%

From the results set forth in Table 1, no correlation between drugcontent and release rate can be readily made.

It was expected that the formulation of Example 3 would release drugfaster than that of Example 1 because of a higher drug content. However,the in-vitro release for Example 3 was slower than expected. It ishypothesized that this is due to the glass transition temperature of thepolymer being lowered (below about 37° C.) by the high drug content.This situation may or may not be translated into in-vivo results.

EXAMPLES 4-9 Spray-Dried

In Examples 4-9, the bupivacaine base and the polymer utilized inExamples 1-3 are once again dissolved in ethyl acetate, but this timethe microspheres are obtained by spray-drying the solution. Example 4utilizes a relatively high drug content, whereas Example 5 utilizes arelatively low drug content. In Examples 7-9, microspheres having asubstantially similar drug content to Examples 4-5 are prepared usingthe solvent extraction technique utilized in Examples 1-3. Details ofthe formulations are presented in Table 2 below.

TABLE 2 Drug Content Formulation (Theoretical) Yield Process Ex. 4 49%55% Spray-Dried Ex. 5 29% 64% Spray-Dried Ex. 6 45% — Spray-Dried Ex. 747% 62% Solvent Extraction Ex. 8 28% 74% Solvent Extraction Ex. 9 60%60% Solvent Extraction

With regard to Example 9, the actual percentage of bupivacaine base inthe microspheres is 51%, the molecular weight of the 50:50 dl-PLGApolymer is 18,000, the microspheres were about 45-63 microns, andin-vitro dissolution conducted as in Examples 1-3 showed that 61% of thebupivacaine was released in 22 hours.

The microspheres of Examples 6 and 9 are suspended in a suitableinjection medium (e.g., water) and then subjected to in-vitrodissolution testing via the procedures set forth in Examples 1-3. Thein-vitro dissolution results are determined for 22 hours.

The in-vitro dissolutions of Examples 4-5 and 7-8 are determined as perthe Examples above, and compared to the dissolution of the bupivacainefree base and the bupivacaine hydrochloride salt forms. When compared topure bupivacaine base, each of Examples 4-5 and 7-8 showed a distinctretarding effect in their dissolution profile. Furthermore, all fourexamples of the invention displayed a small initial burst of drugrelease which was more pronounced in the microspheres prepared by thespray-dried process as compared to the examples prepared by the solventextraction process.

Scanning electron micrographs of the microspheres for the formulationsprepared by the solvent extraction and by the spray-dried technique arethen compared. The spray-dried process yields microspheres which aresmaller than with the solvent extraction process.

EXAMPLE 10 Local Anesthesia Induced by Controlled Release Microspheresis Prolonged by Co-Administration of Dextran Augmenting Agent in theInjection Solution

Microspheres are prepared which contain 75% bupivacaine, by weight. Theduration of local anesthesia induced by the bupivacaine-loadedmicrospheres, prepared from PLGA 65:35, with and without theco-administration of an augmenting agent, is tested in a rat sciaticnerve model for localized local anesthesia. In this procedure, groups ofrats are selected that demonstrate normal behavior in a leg withdrawallatency test at least a week prior to the experimental procedure. Thelatency test determines the time, in seconds, before a rat withdraws itshindpaw from a hotplate set to a safe but uncomfortable temperature (56°C.).

Selected rats are injected with a solution containing a suspension ofbupivacaine-loaded microspheres plus co-administered augmenting agent onone side and injected with a control on the contralateral side so thateach rat serves as its own control. Each injection is adjacent to thesciatic nerve. The controls are bupivacaine-loaded microspheres withoutco-administered augmenting agent and microspheres without anybupivacaine.

A. Sensory Testing

As previously discussed, the degree of sensory local anesthesia ismeasured by determining the time or latency, in seconds, before each ratwithdraws its hindpaw from a hotplate set to a safe but uncomfortabletemperature. Maximum sciatic nerve sensory blockade is defined as havinga latency of about 12 seconds or higher.

B. Motor Testing

The degree of motor blockade is measured by scoring the appearance ofthe affected foot for the signs of loss of motor tone. The assessment isconducted as follows using a 4-point scale based on visual observation:(1) normal appearance, (2) intact dorsiflexion of foot with an impairedability to splay toes when elevated by the tail, (3) toes and footremained plantar flexed with no splaying ability, and (4) loss ofdorsiflexion, flexion of toes, and impairment of gait.

C. Experimental Protocol

Twenty-four rats each receive an injection of bupivacaine-loadedcontrolled release microspheres, into the left or right side,co-administered with a dextran containing injection solution. Thecontralateral side receive either bupivacaine-loaded microspheres at thesame dose, or unloaded microspheres co-administered with a dextraninjection solution.

Sensory hot plate latency is measured from the time of the injectionsuntil the latency declined to under 2 seconds.

Motor blockade is scored until the hind paws of motor blockades ratsreturned to a normal appearance.

The dose of bupivacaine contained in each sciatic nerve injection rangesfrom 5 to 450 mg/kg of rat or about 1.5 to 50 mg at each injection site.

The tested dextrans has a molecular weight ranging from 20 kDa through200 kDa. The injection solution containing dextran is buffered to a pHranging from 7.0 to 8.3.

D. Results

On the sides receiving co-administered dextran augmenting agent show asignificantly longer duration of sensory block and significantlyincreased duration of motor block than do the sides receivingcontrolled-release bupivacaine-loaded microspheres withoutco-administered dextran. Unloaded microspheres with dextran aloneproduce no sensory blockade.

EXAMPLE 11 Local Anesthesia Induced by Controlled Release Microspheresis Prolonged by Co-Administration of Alkalinizing Agents in theInjection Solution

Preparation of microspheres and testing procedures are as describedabove. In this experiment it is shown that co-administration ofalkalinizing agents in the injection solution serve to significantlyprolong the duration of local anesthesia induced by the injection ofcontrolled release bupivacaine-loaded microspheres adjacent to ratsciatic nerve.

A Experimental Protocol

Twenty-four rats each receive an injection of bupivacaine-loadedcontrolled release microspheres into the left or right side, adjacent tothe sciatic nerve, in carbonate-buffered injection solution. Thecontralateral side receives either bupivacaine-loaded microspheres atthe same dose at pH 7.4, or unloaded microspheres with the sameinjection buffer as the treatment side. The pH of the experimentalinjection solution ranges from pH 7.0 through pH 8.3.

B. Results

The degree of sensory and motor local anesthesia show a significantincrease in duration proportional to the alkalinity of thecarbonate-buffered injection solution, with the optimum results obtainedas the pH approached 8.

EXAMPLE 12 Local Anesthesia Induced by Controlled Release MicrospheresWas Prolonged by Co-Administration of Agents With DiversePharmacological Activity

In this example, a large number of pharmaceutical agents were tested foractivity in augmenting the duration of local anesthetic activity.Bupivacaine-containing microspheres at about 75% loading, by weight,were injected perineurally into rat sciatic nerve at a dose of 150mg/kg(weight microspheres/weight rat) to dose of approximately 50 mg/nerve.For the injections, needle placement adjacent to the target nerve wasoptimized by intermittent electrical e stimulation of the target nerve(via the injection needle) with low amplitude current to produce limbflexion. For the injections, the microspheres were suspended in acarrier vehicle suitable for injection. While any pharmaceuticallyacceptable carrier vehicle is acceptable, for these experiments thecarrier vehicle was 1% sodium carboxymethylcellulose and 1% Tween 80 inwater.

Compounds to be tested were co-injected with bupivacaine containingmicrospheres (i.e., mixed as additives into the carrier vehicle) in arange of concentrations. Results are expressed as percent increase induration relative to non-augmented durations that were obtained in thesame animal model.

The duration of anesthesia was measured by the hotplate foot withdrawalmethod described above in Example 10 and refers to the time necessaryfor the animal to recover from maximal nerve latency (12 sec) to alatency of 7 seconds, approximately 50% recovery. The results aretabulated in Table 3 below as percent of control.

TABLE 3 Efficacy of Additives to LAB As Percent of Control WithoutAdditive Duration Principle Anesthesia Pharmacological % Additive AsPercent Activity of Additive Conc. of Control AdditiveAllotetrahydrocortisone 0.05 100 Steroid, Allotetrahydrocortisone 0.5117 GABA receptor modulator Alphaxalone 0.05 169 Steroid, Alphaxalone0.5 123 (GABA receptor modulator and anesthetic Aminopyridine (4-AP)0.05 77 Potassium Aminopyridine (4-AP) 0.11 92 channel blockerAminopyridine (4-AP) 1.09 131 Aminopyrine 0.05 146 Analgesic Aminopyrine0.5 62 Benzamil 0.05 83 Sodium channel Benzamil 0.5 154 inhibitorClonidine 0.05 122 Partial α2 Clonidine 0.5 71 adrenergic agonist andvasoconstrictor. Colchicine 0.1 677, 1308 Microtubule Colchicine 1.0 277inhibitor, inhibitor Colchicine 10 toxic of glucose Colchicine (Placebo)0.1 0 metabolism in Colchicine (no LAB) 10 0 leukocytes (among otherproperties). Dehydroepiandrosterone† 0.05 Steroid, GABADehydroepiandrosterone† 0.5 receptor modulator Dextran 3 46-144 Osmoticpoly- Dextran 6 Anesthesia saccharide continued past end of test periodDiazepam 0.05 231 Modulates GABA Diazepam 0.5 203 receptor Diazoxide0.05 138 Potassium-ATP Diazoxide 0.5 109 channel agonist5,5-diphenylhydantoin 0.05 145, 119 Sodium channel 5,5-diphenylhydantoin0.11 152 inhibitor 5,5-diphenylhydantoin 1.09 138 Minoxidil 0.05 54Potassium channel Minoxidil 0.5 218-265 agonist Ouabain 0.05 154Na,K-ATPase Ouabain 0.5 178 inhibitor Spantide 0.05 119 NeurokininSpantide 0.5 172 antagonist Taxol 0.05 188, 138 Microtubule Taxol 0.11104 assembly promoter Taxol 0.5 82 Taxol 1.09 108 Tetraethylammonium0.05 95 Potassium channel Tetraethylammonium 0.5 123 blocker U-73, 122*0.05 106 PLC inhibitor U-73, 122* 0.5 115 Valproic Acid 0.05 152Potassium channel Valproic Acid 0.5 138 opener Vinblastine 0.05 158Microtubule Vinblastine 0.11 37 inhibitor Vinblastine 1.09 40*(1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-triene-17-yl-]amino]hexl]-1H-pyrrole-2,5-dione)

EXAMPLE 13 Epinephrine as Augmenting Agents

Microspheres containing bupivacaine loaded to about 75 percent by weightwith bupivacaine are prepared, with and without added epinephrine, in apercent loading of about 0.05 percent, by weight, using the methodsdescribed in EXAMPLES 1-3 or EXAMPLES 4-9, above.

Following the protocol set forth i EXAMPLE 10, above, selected rats areinjected adjacent to the sciatic nerve with a solution containing asuspension of bupivacaine-loaded microspheres on the right side, and onthe left side with a solution containing a suspension ofbupivacaine-loaded microspheres and also containing 0.05 percentepinephrine.

Sensory and motor testing is conducted according to sections A and B,respectively, of EXAMPLE 10, above. Using the experimental protocol ofsection C of EXAMPLE 10, 24 rats are tested.

On the sides receiving a combination of bupivacaine and epinephrine incontrolled release microspheres, a significantly longer duration ofsensory block and significantly increased duration of motor block wasobtained than with the sides receiving controlled-releasebupivacaine-loaded microspheres without controlled release epinephrine.

EXAMPLE 14 Amphetamine as Augmenting Agents

In experiments conducted according to EXAMPLE 13, above, amphetamine issubstituted for epinephrine, with the same concentrations of each agent.On the sides receiving a combination of bupivacaine and amphetaminecontaining controlled release microspheres, a significantly longerduration of sensory block and significantly increased duration of motorblock was obtained than with the sides receiving controlled-releasebupivacaine-loaded microspheres without controlled release amphetamine.

EXAMPLE 15 Ephedrine as Augmenting Agent

Microspheres containing bupivacaine loaded to about 75 percent by weightwith bupivacaine are prepared, in a percent loading of about 0.05percent, by weight, using the methods described in EXAMPLES 1-3 orEXAMPLES 4-9, above. In addition, microspheres containing addedepinephrine, in a percent loadings of 0.001 percent, 0.05 percent and 1percent, without bupivacaine, are also prepared according to EXAMPLES1-3 or EXAMPLES 4-9, above.

Following the protocol set forth in EXAMPLE 10, above, selected rats areinjected adjacent to the sciatic nerve with a solution containing asuspension of bupivacaine-loaded microspheres on the right side, and onthe left side with a solution containing a suspension ofbupivacaine-loaded microspheres and also containing epinephrinecontaining microspheres in each dose level.

Sensory and motor testing is conducted according to sections A and B,respectively, of EXAMPLE 10, above. Using the experimental protocol ofsection C of EXAMPLE 10, 24 rats are tested for each of the threeepinephrine dose levels by injecting epinephrine-containing microspheres(same number of microspheres per rat, adjusted for animal weight) atabout the same time as the bupivacaine-containing microspheres areadministered

On the sides receiving a combination of bupivacaine microspheres andepinephrine microspheres, a significantly longer duration of sensoryblock and significantly increased duration of motor block was obtainedthan with the sides receiving controlled-release bupivacaine-loadedmicrospheres without controlled release epinephrine for each dose level,with the effect showing a dose-response curve according toconcentration.

As can be appreciated, a substantial range of pharmaceutical agents iscapable of augmenting the duration of local anesthetic activity. Inaddition, these compounds were tested as additives in the vehiclesuspending the microspheres. Including an augmenting agent into thecontrolled release formulation itself is expected to substantiallyimprove the prolongation of local anesthetic activity by prolonging thepresence of augmenting agent at the anesthetized site.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims. Numerous publications are cited herein, the disclosures of whichare incorporated herein by reference in their entireties.

1. A formulation for inducing sustained regional local anesthesia oranalgesia in a patient comprising: a plurality of substrates in apharmaceutically acceptable medium, said substrates comprising a localanesthetic and an effective amount of a biocompatible, biodegradablecontrolled release material comprising a polymer selected from the groupconsisting of polyanhydrides, copolymers of lactic acid and glycolicacid, poly(lactic) acid, poly(glycolic) acid, polyesters,polyorthoesters, proteins, polysaccharides and combinations thereof toprovide a controlled release of said local anesthetic when saidformulation is implanted or injected in a patient, said biocompatible,biodegradable controlled release material being capable of degrading atleast fifty percent in less than two years following implantation orinjection into the patient and prolonging the release of said localanesthetic from said substrates in-vitro, when measured using the UnitedStates Pharmacopeia/National Formulary Paddle Method II, said substratesbeing included in said formulation in an amount sufficient to obtainreversible local numbness and/or analgesia when said formulation isimplanted or injected in a patient, and taxol in an amount effective toaugment the local anesthetic, said taxol being (i) incorporated intoand/or onto said substrates; or (ii) incorporated into saidpharmaceutically acceptable medium, or (iii) incorporated into saidsubstrates and also incorporated into said pharmaceutically acceptablemedium.
 2. The formulation of claim 1, wherein said substrates aremicrospheres.
 3. The formulation of claim 1, wherein said substrates aremicrocapsules.
 4. The formulation of claim 1, wherein at least a portionof said taxol is incorporated in said substrates.
 5. The formulation ofclaim 1, wherein said taxol is incorporated in the pharmaceuticallyacceptable medium in a concentration of from about 0.01% to about 1%, byweight.
 6. The formulation of claim 1, wherein said taxol isincorporated in the pharmaceutically acceptable medium in aconcentration of from about 0.05% to about 0.5%, by weight.
 7. Theformulation of claim 1, wherein the local anesthetic is incorporatedinto said controlled release material at a percent loading of 0.1% toabout 90% by weight.
 8. The formulation of claim 1, wherein the localanesthetic is selected from the group consisting of bupivacaine,ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine,procaine, chloroprocaine, prilocaine, mepivacaine, mixtures thereof, andsalts thereof.
 9. The formulation of claim 1, wherein the substrates arein a form selected from slabs, rods, beads, pellets, microparticles,spheroids and pastes.
 10. The formulation of claim 1, wherein saidsubstrates include from about 65% to about 80% local anesthetic, byweight.
 11. The formulation of claim 1, wherein said formulation isinjected.
 12. The formulation of claim 1, wherein said formulation isimplanted.
 13. The formulation of claim 1, wherein the local anestheticis bupivacaine.
 14. The formulation of claim 1, wherein the taxol isincorporated in said substrates.
 15. The formulation of claim 1, whereina further amount of said taxol is on said substrates.
 16. Theformulation of claim 1, wherein the taxol is on said substrates.
 17. Theformulation of claim 1, wherein the substrates are in a pharmaceuticallyacceptable medium and wherein the taxol is incorporated in thepharmaceutically acceptable medium.
 18. The formulation of claim 1,wherein the taxol is provided in an amount effective to prolong theduration of the local anesthetic effect for a time period greater thanthat possible by the use of the local anesthetic in controlled releaseform by itself.
 19. A formulation for inducing sustained regional localanesthesia or analgesia in a patient comprising: a plurality ofsubstrates in a pharmaceutically acceptable medium, said substratescomprising a local anesthetic and an effective amount of abiocompatible, biodegradable, controlled release material comprising apolymer selected from the group consisting of polyanhydrides, copolymersof lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic)acid, polyesters, polyorthoesters, proteins, polysaccharides andcombinations thereof to provide a controlled release of said localanesthetic when said formulation is implanted or injected in a patient,said biocompatible, biodegradable controlled release material beingcapable of degrading at least fifty percent in less than two yearsfollowing implantation or injection into the patient, and prolonging therelease of said local anesthetic from said substrates in-vitro, saidsubstrates being included in said formulation in an amount sufficient toobtain reversible local numbness and/or analgesia when said formulationis implanted or injected in a patient; and taxol in an amount effectiveto augment the local anesthetic, said taxol being (i) incorporated intoand/or onto said substrates; or (ii) incorporated into saidpharmaceutically acceptable medium, or (iii) incorporated into saidsubstrates and also incorporated into said pharmaceutically acceptablemedium, said formulation providing an in vitro release of said localanesthetic using the United States Pharmacopeia/National FormularyPaddle Method II of from about 10 to about 60 percent after 24 hours,from about 20 to about 80 percent release after 48 hours and from about40 to about 100 percent release after 72 hours, said formulationproviding a reversible local anesthesia at the site when administered invivo of at least about 24 hours.
 20. The formulation of claim 19,wherein the local anesthetic is selected from the group consisting ofbupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine,xylocaine, procaine, chloroprocaine, prilocaine, mepivacaine, mixturesthereof, and salts thereof.
 21. The formulation of claim 19, whereinsaid Substrates are microspheres.
 22. The formulation of claim 19,wherein said Substrates are microcapsules.
 23. A formulation forinducing sustained regional local anesthesia or analgesia in a patientcomprising a plurality of substrates comprising a local anesthetic,taxol in an amount effective to augment the local anesthetic, and aneffective amount of a biocompatible, biodegradable controlled releasematerial comprising a polymer selected from the group consisting ofpolyanhydrides, copolymers of lactic acid and glycolic acid,poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters,proteins, polysaccharides and combinations thereof to provide acontrolled release of said local anesthetic when said formulation isimplanted or injected in a patient, said biocompatible, biodegradablecontrolled release material being capable of degrading at least fiftypercent in less than two years following implantation or injection intothe patient and prolonging the release of said local anesthetic fromsaid substrates in vitro, when measured using the United StatesPharmacopeia/National Formulary Paddle Method II, said substrates beingincluded in said formulation in an amount sufficient to obtainreversible local numbness and/or analgesia when said formulation isimplanted or injected in a patient.
 24. The formulation of claim 23,wherein the local anesthetic is selected from the group consisting ofbupivacaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine,xylocaine, procaine, chloroprocaine, prilocaine, mepivacaine, mixturesthereof, and salts thereof.